Our overall goal is to provide a better understanding of the neuronal basis of human memory function health and disease. We have taken the unique approach of directly recording single unity activity in humans during memory tasks, using depth electrodes implanted in medial temporal lobe (MTL) structures. This is only possible because our subjects are epilepsy patients who require placement of electrodes in the brain to identify the seizure focus for later resection. We have been successful, in our NIH-funded project (of which this proposal is a continuation), in demonstrating that the approach is not only feasible but also highly productive in terms of revealing some of the key characteristics of neuronal responses to complex visual stimuli during encoding and subsequent retrieval. Now we are in a position to use these data as a foundation for probing further into the neuronal correlates of memory. Specifically, our objective is to characterize neuronal responses during recall processes particularly during stimulus associations and episodic recall. Conscious recall cannot be studies in animals, and this will be the first such investigation at the neuronal level. The central hypothesis states: The same neurons in the hippocampus and entorhinal cortex that demonstrate selective excitatory responses during encoding are reactivated during conscious retrieval. This reactivation occurs when a stimulus or episode is recalled to mind in the absence of a visual stimulus, and also in episodic recall when a cure from the original episode is presented. Furthermore, reactivation has the same stimulus specifically as the original response during encoding and is set against prevalent reduction in neuronal activity ("inhibitory responses") in the hippocampus. It is the balance between excitatory and inhibitory responses that is important for successful retrieval. The specific aims are therefore to (1) compare neuronal responses during encoding with those during recall, (2) compare activity among the various regions of MTL during episodic recall, (3) compare responses of single neurons during recognition and recall, (4) correlate the inhibitory and excitatory responses of single neurons in the MTL to retrieval success, and (5) characterize differences between the epileptogenic hippocampus and contralateral hippocampus with respect to the neuronal responses during the memory tasks. Ours is the only group in a position to address these fundamental questions about the single neuron substrates or declarative memory function in humans. Our findings promise to be of value in understanding memory impairments in Alzheimer's disease, temporal love epilepsy and other neurological disorders involving memory impairment.